A Novel Technology for Connective Tissue Reconstruction
The restoration of structure, function, and physiology to damaged or missing tissue through the use of a regenerative tissue matrix (RTM) leads to regenerative healing rather than reparative scarring. While many processes exist to transform biologic materials into an extracellular matrix (ECM), only those that maintain the required structural and biochemical properties necessary to capture the intrinsic regenerative abilities of the body are suitable to produce an RTM. Histological examination using differential staining with hematoxylin and eosin stain or Verhoeff von Geisen stain of human biopsies of RTM obtained from 2 different abdominal surgery patients taken at 8- and 12 months were consistent with RTM remodeling into fascia-like tissue. A synopsis of recent studies on the use of the RTM GraftJacket® (Wright Medical Technologies, Memphis, Tenn) in successful closure of diabetic foot wounds is presented. Collectively, these reports indicate that LifeCell produced ECMs exemplified by GraftJacket exhibit the required clinical outcomes associated with an RTM.

The goal of regenerative medicine is to recapitulate in adult wounded tissue the intrinsic regenerative processes that are involved in normal adult tissue maintenance. Recent advances allow adult wounds to heal in a similar fashion to the regenerative healing that is also present during fetal development. Research suggests that tissue loss or injury that occurs during early fetal development can be corrected by a regenerative mechanism since fetal wound healing appears to occur without scar formation. However, later in the gestational development there is a transition from the regenerative to the reparative healing process, which utilizes fibrosis and scar formation to replace damaged or otherwise wounded connective tissue. Scar does not have the native structure, function, and physiology of the original normal tissue.

When a wound exceeds a critical deficit it requires a scaffold to organize tissue replacement, and 3 pathways or mechanisms of action may exist for the body to respond to the implanted material (Figure 1). A synthetic material or an extracellular matrix (ECM) that has been intentionally crosslinked to avoid enzymatic degradation will elicit a foreign body response towards the implant resulting in encapsulation. Foreign bodies have an increased potential for long-term infection and extrusion of the implant. When a temporary, resorbable synthetic or a poorly processed ECM is employed for wound closure, an inflammatory response will result in resorption of the implant with the deposition of a reparative scar to close the wound. In contrast, a regenerative tissue matrix (RTM), comprising a structurally and biochemically intact ECM implanted at the wound site, supports the appropriate cascade of cellular events characteristic of tissue regeneration ultimately leading to remodeling and transition of the RTM to tissue resembling that which was lost. Therefore, it is critical to understand these differing mechanisms of action in order to understand how the process for preparing the ECM determines which mechanism of action will be utilized by the body.



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Mechanistic pathways observed for body´s response to implant materials.





While regenerative healing is characterized by the restoration of the structure, function, and physiology of damaged or absent tissue, reparative healing is characterized by wound closure through scar formation. Reparative healing begins with the deposition of a provisional protein scaffold of fibrin as a result of hemostasis. Although transitory in nature, this fibrin scaffold serves to organize the healing process through several functional activities. Initial platelet activation triggers a release of growth factors and other morphogens that become deposited within the fibrin scaffold. In addition to the immobilized growth factors, this scaffold contains cell adhesion proteins that exhibit specific binding to a variety of integrin receptors found on the surface of inflammatory fibroblasts and lymphocytes. These interactions coupled with accommodative protease activity stimulate cell migration into the scaffold. The eventual fibrinolysis and matrix elaboration by the cells within the provisional scaffold along with vascularization of this new connective tissue ultimately results in scar tissue formation. This tissue has a characteristic structure, cellularity, and vascular pattern that are clearly distinguishable from the original, native connective tissue prior to injury. While scar tissue often serves a critical role in the survival of an organism, clinically it is considered a pathological state exhibiting suboptimal functional, biomechanical, and physiological characteristics compared to normal, native connective tissue.

Contrary to the formation of reparative scar, connective tissue structure and physiology are maintained through a process of intrinsic tissue regeneration. Connective tissue is responsible for a variety of functions in the adult human and mesenchymal stem cells that are present in the bone marrow, as well as locally within tissues, are believed to enter the circulation in small quantities ultimately localizing within tissues to provide a rapid source of cells for tissue replenishment and regeneration. Through the integrin class of cell surface receptors these cells recognize and adhere to the extracellular matrix within a tissue or organ. Once bound to specific adhesion sites within the matrix, they commit to a specialized path of differentiation by responding to local growth factors, morphogens, cytokines, as well as local biomechanical forces. Once cellular differentiation has occurred the cells begin remodeling and restoring the matrix within the tissue.